16-fluoromethyl pregnene derivatives



United States Patent 3,223,717 16-FLUOROMETHYL PREGNENE DERIVATIVES Albert Bowers and John Edwards, Mexico City, Mexico,

assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Get. 18, 1960, Ser. No. 63,265 Claims priority, application Mexico, July 12, 1960, 59,144, 59,023 22 Claims. (Cl. 260-3914) The present invention relates to novel cyclopentanophenanthrene derivatives and to a novel process for the production thereof.

More particularly the present invention relates to novel 16a-trifiuoromethyl, 16a-difiuoromethyl and 16a-monofluoromethyl derivatives of the pregnane series and more specifically to derivatives of M-pregnene-LZO-diones which may also have a hydroxy or acyloxy group at (3-17 and/or C-21, halogen or a methyl group at C-6 and unsaturation at C-1, 2 and/or at C-6, 7.

The novel compounds of the present invention which are potent progestational agents with good oral activity as well as are useful intermediates for the preparation of the novel cortical hormones described in our copending application Serial No. 63,267, filed of even date now US. Patent No. 3,155,695, are represented by the following formulas:

Z NC 00;;

CH OR In the above formulas, X represents a trifluoromethyl, difluoromethyl or a monofiuoromethyl group; Z represents a double bond or a saturated linkage between C1 and C-2; Z represents a double bond or a saturated linkage between C6 and C7; R represents hydrogen, methyl, fluorine or chlorine; R and R" represent hydrogen or the acyl radical of a hydrocarbon carboxylic acid of less than 12 carbon atoms, which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to carbon atoms, acyloxy containing up to 8 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and fi-chloropro-pionate.

The novel compounds of the present invention possessing a trifiuoromethyl group at Cl6a may be prepared by a process illustrated by the following equation:

A I ...C F 005 CH CH; (5:0 6:0

0:93 ,1 Hog,

In the above equation, X represents a halogen such as iodine, bromine or chlorine; Ac represents acetyl or other acyl group derived from hydrocarbon carboxylic acids of less than 12 carbon atoms of the type previously mentioned and R, R", Z and Z have the same meaning as heretofore set forth.

In practicing the process outlined above, 3fi-acetoxy- A -pregnadiene-20-one (I) is treated with an excess of trifluoromethyl magnesium halide, preferably trifiuoromethyl magnesium iodide, in a solvent such as tetrahydrofuran or diethyl ether, in the absence or presence of a catalyst such as cuprous chloride, at a low temperature of the order of 30 C. to 20 C., preferably between -20 C. and 10 C., for a period of time ranging from 10 minutes to 5 hours and preferably for 2 to 3 hours to form with simultaneous hydrolysis of the acetoxy group, 16a-trifluoromethyl-A -pregnen8B-ol-ZO-one (II). If one molar equivalent of the trifluoromethylGrrgnard reagent is employed, the acetoxy group remains intact. For introduction of a hydroxyl group at C17a, the latter compound (II) is treated with a mixture of acet c anhydride and acetyl chloride or wi-th acetic anhydride 1n the presence of p-toluenesulf-onic acid to form the enol acetate, 16a-trifluoromethyl-A -pregnadrene-SfiJOB- diol-diacetate (III). Alternatively, when the excess of Grignard reagent is added to the 3B-acetoxy-A pregnadien-ZO-one in the presence of a catalyst such as cuprous chloride, there is formed as the product of the 1,4-addition of the reactive Grignard a mixture of C20 epimer-s of the A -magnesium halide enolate (IV) which upon reaction with acetyl chloride is transformed into the enol acetate, 16u-trifluoromethyl-A pregnadiene-3fl,20-diol diacetate (III).

Upon subsequent reaction of the latter compound with a peracid such as perbenzoic acid, the corresponding 16 trifluoromethyl 5,6; 17,2O-bis-oxido-pregnan-35,20-d1ol diacetate is formed which upon treatment with a base such as methanolic potassium hydroxide is converted into 160: trifluoromethyla,6u-oxido-pregnane-3B,l7a-diol- 20-one (V). The latter is then treated with zinc and sodium iodide in acetic acid to regenerate the C5, 6 double bond and thus form l6a-trifluoromethyl-A -pregnene- 3fi,17a-diol-20-one. The 3/8-hydroxy group of this latter compound is then oxidized to the keto group by conventional treatment with chromic acid in ace-tone and the A double bond is shifted to a A double bond by treatment with dry hydrogen chloride in glacial acetic acid or with oxalic acid in methanol-water solution.

For introduction of an additional double bond at C1, 2, the 16a-trifiuoromethyl-A pregnen-17u-ol-3,20- dione (VI) is refluxed with selenium d oxide preferably in mixture with tertiary butanol and in the presence of catalytic amounts of pyridine or is heated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in dioxane to produce the l6a-trifluoromethyl-A -pregnadien-17ot-ol-3,20- dione (IX: Z=double bond; Z'=saturated linkage; R=hydrogen).

The 6-dehydro derivative of l6a-t-rifluoromethyl-A pregnen-17u-ol-3,20-dione (IX: Z=satura-ted linkage: Z double bond; R=hydrogen) is obtained by reacting the 16st trifluoromethyl A pregnen-17u-ol-3,20'-dione (VI) with chloranil in an inert solvent such as tertiary butanol, xylene or a mixture of ethyl acetate or amyl acetate and acetic acid.

The 1,6-bis dehydro-derivative of l6oc-trifluoromethyl- A -pregnen-l7a-ol-3,20-dione (IX: Z=Z=double bond; R=hydrogen) is obtained either by refluxing the l-dehydro derivative described above with chloranil or by refluxing the 6-dehydro derivative with selenium dioxide or 2,3-dichlo1=o-5,6-dicyano-1,4-benzoquinone.

The 17a-hydroxyl group can be esterified prior to or subsequent to the dehydrogenation of C1, 2 and/or C6, 7 by reacting the 16a-trifluoromethyl-A pregnen- 17a-ol-3,20-dione (VI), or the l-dehydro, 6-dehydro or 1,6-bis-dehydro-derivative thereof (IX) with a hydrocarbon carboxylic acid anhydride of less than 12 carbon atoms in benzene solution and in the presence of p-toluenesulfonic acid.

By m-onoi-odination at C2l of the 16oc-trifluoromethyl A -pregnen-17a-ol-3,20-dione (VI) as by reaction with an excess of iodine in the presence of a base such as solid calcium oxide in mixture with tetrahydro'furan and methanol (as described by Stork et al. in US. Patent 2,874,154), followed by reflux of the thus formed 21-iodo compound with sodium acetate or potassium acetate in mixture With acetone, there is introduced an acetoxy group at CZl to thus form 16ot-trifluoromethyl-A pregnene 17a-2l-diol-3,20-dione-21-acetate v11 Upon reflux of the latter compound with selenium dioxide or 2, dichloro ,6 d cy-ano l,4-benzoq inone, there is formed 16oa-trifluoromethyl-A -pregnadiene-17a,2l-diol- 3,20-dione-21-acetate (VIII: Z=double bond; Z'=saturated linkage; R=hydrogen; R":acetyl). While upon treatment with chloranil in the manner described above. 5 there is formed 16a-trifluorome-thyl-A -pregnadiene- 17a,21-diol-3,20-dione-2l-acetate (VIII: Z=saturated linkage; Z'=double bond; R=hydrogen; R=acetyl). By combining the steps of dehydrogenation, there is formed 160a trifluoromethyl A -pregnatriene-l70,21- diol-3,20-dione-2l-acetate (VIII: Z=Z=double bond; R=hydrogen; R"=acetyl). The ester group is saponified as by treatment with methanolic potassium hydroxide and by conventional esterification with hydrocarbon carboxylic acid anhydrides of the type mentioned previously, other C21 esters are prepared. The tertiary hydroxyl group at C170c can be esterified prior to or subsequent to the dehydrogenation at Cl,2 and/ or C6,7 or prior to the introduction of the ester group at C-21 by reaction With the desired hydrocarbon carboxylic acid anhydride in benzene solution and p-toluenesulfonic acid to form the corresponding dieste'rs (VIII: R and R"=acyl).

The l6a-trifluoromethyl derivatives of A -pregnene-l7a, 2l-diol-3,20-dione, of A -pregnadiene-l7m21-diol-3,2O- dione, of A and of A -pregnatriene-17u,21-diol-3,20- dione can be subjected to microbiological oxidation as by incubation with andrenal glands or with the microorganism Curvularia lunata ATCC 13935, to produce l6ot-trifluoromethyl hydrocortisone, 16a-trifluoromethyl-prednisolone, the 6-dehydro derivatives thereof and finally the 9a-halo substituted derivatives and the ll-keto derivatives as are more fully disclosed in our copending application Serial No. 63,267, filed of even date, now US. Patent No. 3,155,695.

By substituting in the above process the trifluoromethyl magnesium halide by monofluoromethyl magnesium halide there is produced all of the above compounds having a monofluoromethyl group at C16a in place of the trifluoromethyl group. Thus there are produced 16a-monofluoromethy1-A -pregnen-3,B-ol-ZO-one, 16a monofluoromethyl-A -pregnadiene 3,8,20 diol diacetate, 16amonofluoromethyl-5,6,17,20-bis oxido pregnane-3[3,20- diol diacetate, 16u-monofiuoromethyl-5a-6u-oxido-pregmane-3,8,17a-di0l-20-0ne, 16a-monofluoromethyl-A -pregnene-3(3,17a-diol-20-one, 16a-monofiuoromethyl-A -preg- D6II-170t-O1-3,20-di0118, the l-dehydro, 6-dehydro and 1,6- bis-dehydro derivatives of the latter compound as well as the hydrocarbon carboxylic acid esters thereof, l6u-monofluoromethyl 21 iodo-A -pregnen-17-ol-3,20-dione, 16amonofluoromethyl 21 acetoxy-A -pregnen-17a-ol-3,20- dione, 16oz monofluoromethyl-A -pregnene 17a,21-diol- 3,20-dione and the l-dehydro, 6-dehydro, 1,6-bis-dehydro and ester derivatives thereof.

By applying the process outlined'above to 6-methyl- A -pregnadien-3B-ol-20-one acetate (described by PetroW et al., J. Chem. Soc. 4096, 1957) instead of the A pregnadien-3fl-ol-20-one acetate, there are prepared the corresponding compounds having a methyl group at C-6. Thus there is obtained in a consecutive manner the follow ing compounds, a mixture of 0-20 epimers of a magnesium halide enolate of 6-methyl-16ot-trifluoromethyl- A -pregnen-3fl-ol-20-one; 6-methy1-16ot-trifluoromethyl-A pregnen-3B-ol-20-one; the diacetate of 6-methyl-16e-trifluoromethyl-A -3,8,20-diol; the diacetate of 6-methyl-16a-trifluoromethyl-5 ,6; 17,20-dioxido pregnan-3,B,20- diol; 6-methyl-16a-trifluoromethyl-5,6-oxido-pregnan-3B, 17u-diol-20-one; 6-methyl 16m trifluoromethyl-A -pregnen-3fl,17o-diol-20-one; 60c methyl-16a-trifluoromethyl- 17a-hydroxy-A -pregnen-3,20-di0ne; 6a-methyl-l6a-trifluoromethyl-2l-acetoxy-A -pregnen-17x-ol-3,20 dione and 6a-methyl 160a trifluoromethyl-A -pregnadiene-17a,21- diol-3,20-dione, and the corresponding 16a-monofluoromethyl derivatives of the above compounds.

Alternatively, the above novel compounds of the present invention having a trifluoromethyl group at C-1606 5 and a methyl group at C-6a may be prepared by a process illustrated by the following equation:

O3 XI CHgOR CH OR In the above equation, R, R, Z and Z have the same meaning as set forth previously.

In practicing the process outlined above the keto group of 160a trifluoromethyl-M-pregnene 3,8,17a-diol-20-one (VI) is protected by formation of the cyclic ketal by conventional reaction with a glycol such as ethylene glycol, followed by oxidation of the 5(6) double bond with a peracid such as monoperphthalic or perbenzoic acid to form 16a trifiuoromethyl-Sa,6a-oxido-20-ethylenedioxypregnane-3/3-l7u-diol (X). Treatment of the ,6cc-OXidO compound with methyl magnesium halide, preferably methyl magnesium bromide, followed by ammonium chloride decomposition of the Grignard reagent results in the formation of the 6fi-methyl-5a-hydroxy compound and by further treatment with an acid such as p-toluenesulfonic acid in acetone at reflux temperature, hydrolysis of the cyclic ketal group is effected to thus form l6u-trifluoromethyl-6fi-methyl-pregnane-3B,5a,17a-triol-20-one (XI).

Upon oxidation of the latter compound with chromium trioxide in acetone, the 3 8-hydroxy-group is converted into the 3-keto group to produce 16u-trifluoromethyl-6B- methyI- regnane-Sa,l7a-diol-3,20-dione which upon reaction with methanolic potassium hydroxide results in dehydration at C-5 with introduction of the double bond at C4(5 and concomitant inversion of the fits-methyl group to produce 16a-trifiuoromethyl-6a-methyl-A -pregnen-l7aol-3,20-dione (XII) (1fiu-trifiuoromethyl-fiot-methyl-17ahydroxy-progesterone). The latter compound is then converted, stepwise, into the C-2l-iodo, C-21-acetoxy (XIII; R=acetyl) and C-21-hydroxy compound (XIII: R=hydrogen) in the same manner as described for the C6 unsubstituted compound.

A double bond can then be introduced at Cl, 2 in the above compounds as by treatment with selenium dioxide or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and/or at C6, 7 by treatment with chloranil as described hereinabove to form the l-dehydro, 6-dehydro and 1,6-bis-dehydro derivatives of 6a-methyl-l6a-trifluoromethyl-A pregnen-17ot-ol-3,20-dione (XV) and of 6a-methyl-l6atrifluoromethyLM-pregnene-17a,2l-diol-3,20-dione (XIV) and of the esters thereof with hydrocarbon carboxylic acid esters of the type heretofore set forth.

In a similar manner by following the process outlined above there are produced the corresponding 6-methyl-l6amonofiuoromethyl derivatives by substituting the starting material l6a-trifluoromethyl-A -pregnene-313,l7a-diol-20- dione by 16a-monofiuoromethyl-A -pregnene-3B,17a-diol- 20-one.

The novel compounds of the present invention having a trifiuoromethyl group at Cl6a and a fiuoro group at C-6a may be prepared by a process illustrated by the following equation:

I l on; n;

CHzOR In the above formulas, R, R", Z and Z have the same meaning as heretofore set forth.

In practicing the process outlined above, N-brornoacetamide is added to a solution of 16a-trifiuoromethyl-A pregnene-3B,l7a-diol-20-one (VI) in methylene-dichloride-tetrahydrofuran solution containing a large excess of anhydrous hydrogen fluoride. The reaction mixture is maintained at 40 C. for 6 hours to form l6oc-tliflll010- methyl-5u-bromo-6B-fiuoro pregnane-3B,17a-diol-20-one (XVI). Upon oxidation With 8N chromic acid, the 3;?- hydroxy group is converted to the 3-keto group and by subsequent reaction with sodium acetate and methanol, dehydrobromination at C5 is. effected to thusform 6B- (XVII). Upon reaction of the latter compound with a mineral acid, inversion of the steric configuration at C6 is efiected and there is formed 6u-fluoro-16a-trifiuoromethyl-A pregnen-l7a-ol-3,20-dione (XVIII: R=hydrogen). Introduction of a double bond at C-1, 2 and/ or at C-6, 7 by the methods of dehydrogenation described previously results in the formation of 6u-fiuoro-16a-trifluoromethyl-A -pregnadien-17a-ol-3,20-dione (XIX: Z=dou ble bond; Z=saturated linkage; R: hydrogen), 6-fluoro- 16a trifiuoromethyl-A pregnadien 170L-O1-3,20 dione fluoro-l6u-trifluoromethylM-pregnen 170L-Ol-3,20-dlOI1e (XIX: Z==saturated linkage; Z=double bond; R =hydrogen), and 6-fluoro-l6ot-trifluoromethyl-A -pregnatrien- 17oc-Ol-3,20-di0ne (XIX: Z=Z=double bond; R=hydrogen).

Esterification of the tertiary hydroxyl group at C-17a in the above compounds (XVIII and XIX) is efiected by reaction with hydrocarbon carboxylic acid anhydrides containing less than 12 carbon atoms in benzene solution and in the presence of p-toluenesulfonic acid.

The C-2l hydroxy group is introduced into the 6w fluoro 16a trifiuoromethyl-A pregnen-l7a-ol-3,20-dione compound (XVIII) or the ester derivative thereof by the method of Stork et al., US. Patent 2,874,154 and Ringold et al., I. Am. Chem. Soc. 80, 250 (1958) to form the 6u-fluoro-16a-trifluoromethyl-A -pregnen-17a,21- diol-3,'20-dione (XX: R"=hydrogen). The latter is converted into the A A A -bis-dehydro-deriv-atives (XXI: R=R"=hydrogen) by the methods of dehydrogenation described above. Conventional esterification with hydrocarbon carboxylic acid anhydrides or chlorides results in the formation of the C-21 esters (XX and XXI: R"=acyl; R=hydrogen). Esterification of the tertiary hydroxyl group at C17a is ettected with the desired acid anhydride in benzene and p-toluenesulfonic acid to thus form diesters (XXI: R=R"=acyl) having the same or different ester groups depending upon the acid anhydride that is employed.

The novel compounds of the present invention having a monofiuoromethyl group at C-l6oc and a fluoro group at C-6u may be prepared in the same manner described above for the l6a-trifluoromethyl series by starting with 16m monofiuoromethyl A -pregnene-3B,17a-diol-2O-one instead of the corresponding 16a-trifiuoromethyl compound.

Alternatively the fluoro group may be introduced at C-6 by esterifying 16a-rnonoflu0r0rnethyl or l6a-trifluoromethyl A -pregnen-3fl,l7a-diol-20-one with acetic anhydride by conventional methods to produce the corresponding 3fi-acetate. Upon further esterification with a hydrocarbon carboxylic acid of less than 12 carbon atoms in benzene solution and in the presence of p-toluenesulfonic acid, there is formed the 16a-monofluoromethyl or 16a-trifluoromethyl-A pregnen-3[i,17a-diol-20- one-diacylate. By treatment with dilute methanolic potassium hydroxide, the acetoxy group at C-BB is selectively saponified and there is formed l6a-monofluoromethyl or 16tx-trifiuoromethyl-A -pregnene-3B,17adiol-29-one-17-acylate. Upon treatment of the latter compound with a peracid such as monoperphthalic or perbonzoic acid the 5,6 double bond is oxidized and there is formed the 5a,6a-oxido-l6u-monofluoromethyl or 1600 trifiuoromethyl pregnane-3B,17a-diol-20-one 17aacylate. Upon reaction of the latter compound with boron trifluoride the oxido ring is opened and there is formed l-6u-monofiuoromethyl or l6a-trifiuoromethyl- 6B fluoro pregnane-3B,5u,l7u-triol-20 one l7a-acylate. Upon oxidation of the latter compound with chromic acid, the 3 3-hydroxy group is converted into the 3-keto group and by further reaction with concentrated hydrochloric acid, dehydration at C-5 is effected with simultaneous inversion of the steric configuration at 0-6 to form l6ot-monofiuoromethyl or 16a-trifluorornethyl-6afluoro-M-pregnen-l7ot-ol-3,ZO-dione-acylate. Dehydrogenation at C-l,2 and/ or at C-6,7 is effected by treatment with selenium dioxide or 2,3-dichloro-5,=6-dicyano-1,4- benzoquinone, and/or chloranil in the manner described previously to produce the l-dehydro, 6-dehydro or 1,6-bis-dehydro-derivatives. The C-21 hydroxy group may then be introduced by the method described by Stork et al. and Ringold et al., supra.

The following equation exemplifies in part the above process as applied to the 16a-monofluoromethyl derivative:

CH3 CH3 N fij-CHJ \fi-CHE Esterification A00 AcO- l, (1) Hydrolysis (2) peracid @ydrogenation In the above equation, R' represents a hydrocarbon carboxylic acyl group of the type previously described Ac, Z and Z have the same meaning as heretofore set forth.

The novel compounds of the present invention having a trifluoromethyl group at C16a and a chloro group at C6zx may be prepared by a process illustrated by the following equation:

E I c=o e:

: XXIV t 5);. dfi

In the above formulas, R, R", Z and Z have the same meaning as previously set forth.

In practicing the process outlined above, 16oc-t1iflu0l0- methyLM-pregnenc-Sfl,l7a-diol-20-one (VI) is reacted with a peracid such as monoperphthalic or perbenzoic acid to oxidize the 5(6) double bond to form l6a-trifluoromethyl 511,60: oxido pregnane-3fi,l7a-diol-20-one (XXII). Upon reaction of the latter compound with concentrated hydrochloric acid in glacial acetic acid there is formed 1'6a-trifluoromethyl-6B-chloro-pregnane-3;8,5 x, 17a-trio1-20-one (XXIII), which upon oxidation with chromic acid is converted into 16a-trifluoromethyl-6fichl0ro-pregnane-5x,17a-diol-3,20-dione. Treatment of the latter compound in glacial acetic with dry hydrochloric acid results in dehydration and in the inversion of the steric configuration at C6 and there is aiforded 16a-trifluoromethyl 6oz chloro A pregnen-l7a-ol-3,ZO-dione (XXIV) which can be further dehydrogenated at Cl,2 and/ or C6,7 by the methods described previously to yield 16u-trifiuoromethyl-6a-chloro-A -pregnadien- 17a-0l-3,20-dione (XXV: Z=double bond; Z=saturated linkage; R=hydrogen); 16oz trifluoromethyl 6 chloro- A -pregnadien-l7u-ol-3,20-dione (XXV: Z=saturated linkage; Z'=double bond; R=hydrogcn) and 16a-trifiuoromethyl 6-chloro A -pregnatrien-17a-ol-3,2O-dione (XXV: Z=double bond; R=hydrogen).

The 16a-trifluoromethyl-6ot-chloro-A -pregnen-17a-ol-3- 20-dione (XXIV) is converted, stepwise, into the C121 iodo, C-21-acetoxy (XXVI: R" =acetyl; R=hydrogen; Z=Z'=satuarted linkage) and C21 hydroxy compound (XXVI: R" =R=hydrogen; Z=Z'=s-aturated linkage) by the method of Stork et al. and Ringold et al., supra.

Upon conventional esterification with hydrocarbon carboxylic acid anhydrides or chlorides of the type previously mentioned, there are formed the C21 esters. The tertiary hydroxyl group at C-17a is esterified in the manner described heretofore either prior to or subsequent to the dehydrogenation steps or the introduction of the C-21 hydroxy moiety to form the esters of compounds XXV and XXVI.

By substituting in the process outlined above the 16:1- trifiuoromethyl-A -pregnene-3,8,l7a-diol-20-one by monofluoromethyl-A -pregnene-3 3,17u-diol-20-one, there are produced the corresponding l6a-monofluoromethyl compounds.

Alternatively the 6oc-Ch1010 group may be introduced by treating the ester of l6atrifluoromethyl-A -pregnenl7a-ol-3,20-dione (IX: Z=Z'=satur-ated linkage; R=acyl) or the corresponding l6a-monofiuoromethyl derivative with ethyl orthoformate to form the enol ether, 16oc-t1'ifiuoromethyl or 16a-monofiuoromethyl-3-ethoXy-A -pregnadien-17u-ol-20-one-acylate. Upon treatment of the latter in acetone and sodium acetate with N-chlorosuccinimide and acetic acid there is obtained l6a-trifluoromethyl or 16rx-monofiuorornethyl-Gfl-chloro-17aacyloXy-A -pregnene-3,ZO-dione, which, upon further reaction with concentrated hydrochloric acid and acetic acid results in inversion of the steric configuration at C6 to form l 6a-trifluoromethyl or 16cc-1110I10fl110l0- methyl 6a chloro-l7a-acyloxy-A -pregnene-3,20=dione. Further reaction with solenium dioxide or 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone and/or chloranil results in dehydrogenation at C-'l,2 and/or C6,7. By applying the method of Stork et al. or Ringold et al., described above, there is introduced a hydroxy group at C21 which may be further esterified with hydrocarbon carboxylic acid anhydrides by conventional methods.

The novel compounds of the present invention possessing a difluoromethyl group at Cl6tx are prepared by a process illustrated by the following equation:

XXVI

\(1) oxalyl chloride (2) lithium aluminu1n\ tertiary butoxide CH3 (I i-A0 U... 3. or.

OHa

U I z l fl In the above formulas, Ac, R, R", Z and Z have the same meaning as previously set forth.

To practice the process outlined above, the starting material, the S-benzoate-ZO-acetate of A -pregnene-35.20B diol 160a carboxylic acid is prepared by treating 161xcyano-A -pregnen3l3-ol-20one acetate, described by J. Romo, Tetrahedron 3, 37 (1958), with sodium borohydride to reduce the C-keto group to the C-20 hydroxyl group which is then etherified by reaction with dihydropyran in benzene solution and in the presence of p-toluenesulfonic acid. The thus formed ZOB-tetrahydropyranyloxy-l6u-cyano-A -pregnen-3fl-ol-acetate is hydrolyzed by refluxing with methanolic potassium hydroxide, followed by benzoylation by conventional reaction with benzoyl chloride to afford the 3-benzoyloxy-205-tetrahydropyranyloxy-A -pregnene-16oc-carboxylic acid. Hydrolysis of the tetrahydropyranyl ether moiety as by reaction of the latter compound in acetic acid with dilute hydrochloric acid followed by acetylation of the thus formed C-ZOfi alcohol by conventional means affords the starting material, the 3-benzoate-20-acetate of A -pregnene-3,8-20,B-diol-16u-carboxylic acid (XXVI). Treatment of the latter compound with oxalyl chloride followed by reduction of the thus formed acid chloride of XXVI by the reaction with lithium aluminum t-butoxide or by the method of Rosenmund results in the formation of the 3-benzoate-20-acetate of A -pregnene-3(3,20B-dioll6a-carboxaldehyde (XXVII). The latter compound is then reacted with a large excess of sulfur tetrafluoride in benzene solution for a period of time in the order of 48 hours to effect replacement of the l6a-carboxaldehyde group by the difluoromethyl group and thus form 16adifluoromethyl-A -pregnene-3[3, 20fl-di0l-3 benzoate 20- acetate (XXVIII). The acetate group is preferentially saponified as by treatment with methanolic potassium carbonate, followed by oxidation of the thus formed C-ZO alcohol with 8 N chromic acid to produce l6a-difluoro methyl-A -pregnen-3 3-ol-20-one-benzoate (XXIX) which upon saponification with methanolic potassium hydroxide is converted into l6a-difiuoromethyl-A -pregnen-3/3-ol-20- one. The latter compound is subjected to oxidation under Oppenauer conditions to thus form 16a-difluoromethyl progesterone (XXX).

For introduction of a hydroxy group at C-17oc, the difluoromethyl-A -pregnen-3B-ol-20-one benzoate (XXIX) intermediate described above is treated in the same manner as the l6a-trifluoromethyl compound. This reaction of the intermediate compound with acetic anhydride and p-toluenesulfonic acid results in the formation of the enol acetate, 16a-difluoromethyl-A -pregnadiene- 313,20i3-diol-3-benzoate,-20-acetate (XXXI). Upon subsequent reaction with a peracid such as monoperphthalic acid, the corresponding 16a difiuororne-thyl-5,6;17,20- dioxido-pregnan 3,6 2O diol,3-benzoate-20-acetate is formed which upon treatment with a base such as dilute methanolic potassium hydroxide under an atmosphere of nitrogen is converted into 1600 difiuoromethyl-5a,6aoxido-pregnane-Blfi,l7u-diol-20-one (XXXII). The latter is then reacted with zinc and sodium iodide in acetic acid to regenerate the 5(6) double bond and the thus formed l6a-difiuoromethyl-M-pregnene-3,8,l7a-diol-20-one is subjected to oxidation with 8 N chromic acid followed by treatment with oxalic acid to form l6a-difluoromethyl-A pregnen 17oz ol-3,20-dione(16u-difluoromethyl-17a-hydroxy-progesterone) (XXXIII). By monoiodination at C2l of the l6a-difluoromethyl-A -pregnen-17a-ol-3,20- dione as by treatment with an excess of iodine in the presence of calcium oxide as described previously, followed by reaction with potassium acetate in mixture with acetone, there is formed l6a-difluoromethyl-M-pregnene- 1711,21-diol-3,20-dione-21-acetate (XXXV) which upon saponification with methanolic potassium hydroxide is converted into the free diol.

Esterification of 16a difiuoromethyl-17a-hydroxy-A pregnene-3,20-dione (XXXIII) is effected by reaction with the desired hydrocarbon carboxylic acid anhydride of less than 12 carbon atoms of the type previously mentioned in benzene solution and in the presence of p-toluenesulfonic acid to afford the '16a-difluoromethyl-17aacyloxy-A -pregnene-3,20-dione compound (XXXIV; Z and Z'=saturated linkage). By treating 16u-difluoromethyl-17a-hydroxy-M-pregnene-B',ZO-dione (XXXIII) or the 17a-ester derivative (XXXIV; Z and Z=saturated linkage) with selenium dioxide or with 2,3-dichloro-5,6- dicyano-1,4-benzoquinone, dehydrogenation is effected at C-1,2 to form the 16a-difluoromethyl-17a-hydroxy-A pregnadiene-3,20-dione (XXXIV; R=hydrogen; Z=double bond; Z satur-ated linkage or the 17-ester derivatives (XXXIV; R=acyl; Z=double bond; Z =saturated linkage). Further dehydrogenation at C-6,7 is effected by the reaction with a quinone having an oxidation-reduction potential of less than 0.65 such as chloranil, in a solvent such as xylene, t-butanol, or a mixture of ethyl acetate or amyl acetate and acetic acid to thus form 1604- difluoromethyl 17cc hydroxy A -pregnatriene-3,20- dione (XXXIV; R=hydrocarbon; Z=Z=double bond) or the 17-ester derivatives (XXXHI;R=acyl; Z=Z=double bond). Alternatively, dehydrogenation can first be effected at C-6,7 to afford 16a-difiuoromethyl-17a-hydroxy-A -pregnadiene 3,20'dione (XXXIV, R=hydrogen; Z=saturated linkage; Z=double bond) or the 17- ester derivative thereof (XXXIV; R=acyl; Z=saturated linkage; Z=double bond). The latter compounds can then be further d-ehydrogenated at C-l,2 as by reaction with selenium dioxide to obtain the same A -pregnatriene compounds set forth above.

For preparation of the novel compounds of the present invention having a difluoromethyl group at C-16a and a methyl, chlorine or fluorine group at C-6a there is first produced the 1611 difluoromethyl-A -pregnene-3B,17adiol 20 one by reacting 16a-difiuoromethyl-5,6-oxidopregnane-BB,l7ut-diol-20-one (XXXII) with zinc and sodium iodide to regenerate the 5(6) double bond. By subjecting the thus formed 16tat-difluoromethyl-A -pregnene- 3,8,17a-diol-20-one to the same reactions as set forth for the corresponding 16:! trifluoromethyl-A -pregnene-35, 17a-diol-20-one there are produced the corresponding compounds having a difluoromethyl group at C-l6oc and a methyl, fluorine or chlorine substituent at C-6a. Alternatively, a methyl or chlorine substituent can be introduced directly into the 160t-d1flHOI'OInBthy1-50t,60t-OXIdO- pregnane'3fi,17a-diol-20-one, obtained by crystallization of the mixture of 5,6-epoxides (XXXII) by the same methods described in the 16a-trifiuoromethyl series to obtain the corresponding 6-methyl and 6-chloro-l6u-difiuoromethyl derivatives.

There are thus produced the 6a-methyl, 6a-fiuoro and 6ot-chloro derivatives of 16a-difluoromethyl-A -pregnene- 17cc o1 3,20-dione, of 16a-difiuoromethyl-A -pregnadiene-17a-ol-3,20-dione, of 16a-difluoromethyl-A pregnene 17a,21diol-3,20-dione, of 16ot-difiuoromethyl-A pregnadiene 1711,21 diol-3,20-dione and of the esters thereof with hydrocarbon carboxylic acid anhydrides containing less than 12 carbon atoms. There are also formed the 6-methy1, 6-fiuoro and 6-chloro derivatives of 16oc-difiuoromethyl-A -pregnadien-17a-ol-3,20-dione, of 160cdifiuoromethyl A pregnatrien-17at-ol-3,20-dione, of 1600 difluoromethyl A pregnadien-17a,21-diol-3,20- dione and of 16ot-difluoromethyl-A -pregnatrien-17ot,21- diol-3,20-dione and the hydrocarbon carboxylic acid esters thereof.

The following examples serve to illustrate but are not intended to limit the present invention:

Preparation of trifluoromethylmagnesium iodide' By following the method of Haszeldine (J. Chem. Soc. 1257, 1954), there was prepared a filtered solution of trifiuoromethyl magnesium iodide in tetrahydrofuran, starting from trifluoroiodomethane (Columbia Organic Chemicals Corporation). Using 2 g. of magnesium, 5 g. of trifiuoroiodomethane and 150 cc. of tetrahydrofurane there was obtained a solution containing 3.0 g. of the desired reagent, which solution was kept at a temperature of -30 C.

Preparation 0] mono fluoromethylmagnesium iodide By following the method of Arkel and Janetsky (Rec. Trav. Chim. 56, 167 (1937)) there was prepared fluoroiodomethane; this compound was treated with magnesium in tetrahydrofuran, according to the method described by Haszeldine (J. Chem. Soc. 1275 (1954)) in order to obtain monofluoromethylmagnesium iodide. Using 2 g. of magnesium, 5 g. of fiuoro-iodomethane and 150 cc. of tetrahydrofuran there was obtained a solution containing 3.0 g. of the desired reagent; there were prepared several batches of the above solution and kept at a temperature of approximately 30 C.

EXAMPLE I To 150 cc. of tetrahydrofuran containing 3 g. of trifiuoromethylmagnesium iodide was added a solution of 5 g. of the acetate of A -pregnadien-3,6-ol-20-one in 50 cc. of tetrahydrofurane and 0.7 g. of cuprous chloride. The addition was effected under stirring, over a period of 30 minutes, under an atmosphere of nitrogen and at a temperature between 20 C. and -10 C. The mixture was stirred for a further 2 hours at 0 C. cooled to -30 C. and treated with 10 cc. of acetyl chloride. The temperature was allowed to reach 0 C. and the mixture was kept at this temperature for 20 minutes. There was then added cc. of aqueous saturated ammonium chloride solution followed by 30 cc. of aqueous concentrated sodium acetate solution. Extraction with methylene chloride followed by conventional purification afforded 3.75 g. of 3,8,20 diacetoxy-l6a-trifluoromethyl-A -pregnadiene.

For the next step there were combined several batches of the above compound.

A solution of 10 g. of 35,20-diacetoxy-16a-trifluoromethyl-A -pregnadiene in 100 cc. of ether was treated with 300 cc. of a 1 N solution of monoperphthalic acid and the mixture was kept at room temperature for 3 days; at the end of this time it was consecutively washed with dilute sodium chloride solution, sodium carbonate, sodium iodide, sodium thiosulfate and finally with sodium chloride solution; the ether solution was dried over anhydrous sodium sulfate and evaporated to dryness, thus yielding a mixture of 5a,6u-17,20-bi$ oxido-l6ot-trif1uoromethyl-3fl, 20-diaoetoxy-pregnane and of its 55,6,8-isomer. This mixture was dissolved in 400 cc. of methanol, treated with 5.4 g. of potassium carbonate dissolved in cc. of water and refluxed for 1 /2 hours; the mixture was neutralized with acetic acid, concentrated to of its volume, poured with ice water and the precipitate formed was collected and dried.

EXAMPLE II The above crude product was added to a mixture of 8.5 g. of sodium iodide, 2.8 g. of anhydrous sodium acetate, 8.5 g. of zinc dust, 33 cc. of acetic acid and 1.2 cc. of water; the mixture was stirred at room temperature for 3 hours, the zinc was removed by filtration and the solution was poured into ice water. The precipitate formed was collected, washed with water to neutrality, dried, dissolved in 200 cc. of hot dimethyl-formamide, filtered through celite to remove traces of zinc and then hot water was added to crystallize the product; after cooling in ice the precipitate was collected by filtration and washed with methanol, thus affording 5 g. of 16a-trifiuoromethyl-A pregnene-3p,17u-diol-20-one.

EXAMPLE III 5 g. of the above compound were dissolved in 50 cc. of acetone, cooled to 0 C., flushed with nitrogen and treated under stirring with 8 N chromic acid solution, added in a thin stream, at 0 C., until the red color of chromium trioxide persisted in the mixture. (The 8 N solution of chromic acid was prepared by dissolving 26.7 g. of chromium trioxide in 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.) After diluting the mixture with water the product was collected by filtration, washed with water and dried under vacuum.

The crude product was dissolved in 200 cc. of methanol and treated at room temperature with a solution of 0.5 g. of oxalic acid in 5 cc. of water. The mixture was kept standing for 3 hours, then treated with water and to neutral and dried. There Was thus obtained 16a-trifluoromethyl-17u-hydroxy-A -pregnene3,20-dione.

EXAMPLE IV To a solution of 3.9 g. of 16a-trifluoromethyl-17ot-hydroxy-A -pregnene-3,20-dione in 30 cc. of tetrahydrofurane and 18 cc. of methanol was added under vigorous stirring 6 g. of calcium oxide and then 6 g. of iodine; the stirring was continued at room temperature until the color of the solution became pale yellow and then the mixture was poured into ice water containing 15 cc. of acetic acid and 2.1 g. of sodium thiosulfate, stirred for 15 minutes, most of the liquid was separated by decantation and the precipitate was collected, washed with water and dried under vacuum. There was thus obtained 16x-trifluoromethyl-17a-hydroxy-21-iodo-A -pregnene-3,20-dione.

The above substance was mixed with 105 g. of anhydrous acetone and 12 g. of recently fused potassium acetate and refluxed for 8 hours, concentrated to a small volume under reduced pressure and diluted with water; the product was extracted with ether, washed with water, dried over anhydrous sodium sulfate and the ether was evaporated. Recrystallization of the residue from acetone-hexane yielded the 2l acetate of 16x-trifluoromethyl- A -pregnene-17a,21-di0l-3,20-dione.

EXAMPLE V A mixture of 1.16 g. of the above compound, 120 cc. of t-butanol, 2 cc. of pyridine and 600 mg. of selenium dioxide was refluxed under an atmosphere of nitrogen for 72 hours; after cooling the mixture was diluted with ethyl acetate and filtered through celite; the filtrate was evaporated to dryness under reduced pressure, the residue was triturated with water and the solid collected, washed with water and dried. Recrystallization from methylene chloride-hexane afforded 560 mg. of the 21-acetate of 16atrifiuoromethyl-N -pregnadiene-l7a,21-diol-3,20-dione.

EXAMPLE VI A solution of the above compound in 20 cc. of methanol was mixed with 5.6 cc. of a 1% solution of potassium hydroxide in water and stirred at C. under an atmosphere of nitrogen for 1 hour; it was then neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the'solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus giving approximately 475 mg. of 16oc-trifiuoromethyl-A -pregnadiene-17ot,21-diol-3,20-dione.

EXAMPLE VII A solution of 4 g. of the acetate of 16u-trifluoromethyl- A -pregnene-17a,2 1-diol-3,20-dione, obtained in accordance with the method of Example 1V, in 150 cc. of methanol and 15 cc. of a 4% aqueous solution of potassium hydroxide was stirred for 1 hour under an atmosphere of nitrogen at 0 C.', the mixture was neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected, washed with Water, dried and recrystallized from ethyl acetate-methanol, thus producing 3.05 g. of 16a-trifluoromethyl-A -pregnene-17a,21-diol-3,20-dione.

EXAMPLE VIII To a polyethylene bottle containing 119 g. of anhydrous tetrahydrofuran was added 70 g. of anhydrous hydrogen fluoride. The mixture was cooled to 70 in a Dry Iceacetone bath and, undervigorous stirring there was added a mixture, previously cooled to 7() C., of 10 g. of 161 trifluoromethyl A pregnene 35,170 diol-20-one (described in Example II), and 5.0 g. of N-bromoacetamide in 350 ml. of anhydrous methylene chloride distilled over calcium chloride. The mixture was stirred at -70 C. for 5 hours, poured into aqueous saturated sodium carbonate solution and the precipitate was filtered. The organic layer was separated, the aqueous phase was extracted with several portions of methylene chloride and the extracts were combined, washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The original precipitate and the residue of the evaporation were combined and crystallized from acetone, thus affording 9.3 g. of 16a-trifluoromethyl-5ubromo-6B-fluoro-pregnane-3fl,17a-diol-20-one.

EXAMPLE IX A solution of 2 g. of the above compound in 100 cc. of acetone was cooled to 0 C. and treated under an atmosphere of nitrogen under stirring with a solution of 8 N chromic acid (prepared as in Example III) until the color of the reagent persisted in the mixture. The mixture was then stirred for 2 minutes more at ()5 C., diluted with water and the precipitate was collected, washed with water and dried under vacuum, thus affording 5a-bromo-6fifluoro-16a-trifiuoromethyl-pregnan-l7a-ol-3,20-dione.

EXAMPLE X The above product was dissolved in methanol and the reaction mixture was treated with 4 g. of anhydrous sodium acetate and refluxed for 2 /2 hours. The mixture was evaporated to dryness under reduced pressure, water was added to the residue and the precipitate that formed was collected, washed with water, dried and treated with decolorizing charcoal in acetone solution. The charcoal was removed by filtration, the acetone was evaporated and the residue was crystallized from ethyl acetate-hexane. There was thus obtained 6B-fluoro-16a-trifiuoromethyl-A -pregnen-17a-ol-3,ZO-dione.

A slow stream of dry hydrogen chloride was intro-duced for 4 hours into a solution of 1 g. of the above compound in 100 cc. of glacial acetic acid, maintaining the temperature around 20 C. The mixture was then poured into ice water and the precipitate was collected by filtration,

washed with water, dried and recrystallized from ethyl acetate-hexane thus yielding 60t-fiUO1'O-160t-llI'lflllDlOITl6thyl-A -pregnen-17a-ol-3,20-dione.

EXAMPLE XI A mixture of 1.5 g. of the above compound, cc. of tertiary butanol, 2 cc. of pyridine and 600 mg. of selenium dioxide was refluxed under an atmosphere of nitrogen for 72 hours. After cooling, the mixture was diluted with ethyl acetate and filtered through celite, the filtrate was evaporated to dryness under reduced pressure, the residue was triturated with water and the solid collected, washed with water and dried. Recrystallization from methylene chloride-hexane afiorded oa-fluoro-l6a-trifluoromethyl- A -pregnadien-17a-ol-3,2O-dione.

EXAMPLE XII By following the method described in Example IV except that the 16a-trifiuoromethyl-17a-hydroxy-A -pregnone-3,20-dione was substituted by 6a-fluoro-16ot-trifluorornethyl-17a-hydroxy-A -pregnene-3,20-dione (prepared in Example X), there were produced 6oc-fll101'O-16oc-tfifiLlOI0- methyl-l7a-hydroxy-21-iodo-A -pregnene-3,2O-dione and 6a-fluoro-16a-trifiuoromethyl-A -pregnene-17a,21 diol 3,20-dione-21 acetate.

Upon treatment of the latter compound in methanol with potassium hydroxide as described in Example VI, there was obtained 6u-fluoro-16m-trifiuoromethyl-A -pregnene-17a,21-diol-3,20-dione.

EXAMPLE XIII By applying the method of dehydrogenation described in Example V, 6a-fluoro-16a-trifluoromethyl-A -pregnene- 1704,21-di0l-3,20-dione-2l-acetate and the free alcohol thereof (described in the preceding example) were converted into the corresponding l-dehydro derivatives.

EXAMPLE XIV The methods described in Examples I through VII were repeated starting from the acetate of the 6-methyl deriva- EXAMPLE XV A mixture of 10 g. of 16a-trifluoromethyl-A -pregnene- 3,8,17a-diol-20-one (cf. Example II), 80 cc. of ethylene glycol, 2 liters of dry benzene and 1.5 g. of p-toluenesulfonic acid monohydrate was refluxed for 18 hours, using a Dean-Stark water separator. The cooled mixture was treated with 5% aqueous sodium bicarbonate, the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Crystallization of the residue from acetone afforded 16oztrifluoromethyl-2O-ethylenedioxy-A -pregnene-3B,17a-diol.

A solution of 8 g. of the above compound in 1600 cc. of methylene chloride was cooled to C. and mixed with an ether solution of 4.0 g. of monoperphthalic acid. The mixture was kept at 0 C. for 16 hours, then diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutrality, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by crystallization from acetone-hexane. There was thus obtained 16ot-trifluoromethyl-5a,6ot-oxido-20 ethylenedioxypregnane-3 fi,l7a-diol.

A mixture of 5 g. of the above compound and 5 molar equivalents of methylmagnesium bromide in 500 cc. of dry benzene was refluxed for 3 hours, then poured under vigorous stirring into a mixture of 1 liter of 20% aqueous ammonium chloride solution and 1 kg. of ice. The benzene layer was separated, washed with water, dried over anhydrous sodium sulfate and the benzene was evaporated, finally under reduced pressure. The residue was treated with 100 mg. of p-toluenesulfonic acid monohydrate and 300 cc. of acetone and kept at room temperature for 16 hours, diluted with water and the solid collected, thus giving the crude 6fi-methyl-l6ot-trifluoromethyl-pregnane- 3B,5tt,17a-triol-20-one. The latter was oxidized with 8 N chromic acid, in accordance with the method described in Example III, to produce 6fi-methyl-l6a-trifiu- Oromethylregnane-Sa,17a-diol-3,20-dione, which, without further purification, was treated with 250 cc. of 1% methanolic potassium hydroxide under an atmosphere of nitrogen and at room temperature for 8 hours. After acidifying with acetic acid the mixture was concentrated to a small volume under reduced pressure and the product was precipitated by the addition of water. The solid was collected, washed with water and crystallized from acetonehexane. There was thus obtained 6u-methyl-l6atrifluoromethyl-A -pregnen-17ot-ol-3,20 dione, identical with the intermediate of Example XIV.

EXAMPLE XVI 1 g. of 16a-trifluoromethyl-17a-hydroxy-A -pregnene- 3,20-dione (Example III) was allowed to react overnight at room temperature with 5 cc. of acetic anhydride and 1 g. of p-toluenesulfonic acid in 50 cc. of acetic acid. The mixture was then poured into ice water and the solid formed was collected, washed with water, dried and treated with 50 cc. of 1% methanolic potassium hydroxide, under an atmosphere of nitrogen, at 5 C. for 4 hours. It was acidified with acetic acid, concentrated to a small volume and the precipitate was collected, washed with water, dried and crystallized from acetonehexane. There was thus obtained 17a-acetoxy-A -pregnene-3,20-dione.

By following the procedure described above there was acetylated the 17a-hydroxyl group of the IGa-trifluoromethyl16u-fluoro and 6u-methy1-16a-trifluoromethyl derivatives of l7ot-hydroxy-A -pregnene-3,20-dione.

EXAMPLE XVII A mixture of 1 g. of 16u-trifiuoromethyl-17a-hydroxy A -pregnene-3,20-dione, 3 g. of caproic anhydride, cc. of anhydrous benzene and 500 mg. of p-toluenesulfonic acid monohydrate was kept at room temperature for 48 hours, then abundantly washed with 5% aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the residue on neutral alumina followed by crystallization of the solid eluates from acetone-hexane afforded the caproate of 16a-trifiuoromethyl-l7a-hydroxy- M-pregnene-LZO-dione.

By the same process there were prepared the caproates of l6aatrifiuoromethyl-6a-fluoro-17a-hydroxy-A -pregnene-3,20-dione and of 16a-trifluonomethyl-Got-methyl- 17ot-hydroxy-A -pregnene-3,20-dione.

EXAMPLE XVIII The reaction with trifiuoromethyl magnesium iodide described in Example I was repeated starting from 5 g. of the acetate of A -pregnadien-3fi-ol-20-one, but without acetylating, the reaction mixture was poured into 1 l. of ice water containing 100 g. of ammonium chloride, the tetrahydrofuran was distilled and the aqueous residue extracted with several portions of ether. The extract was washed with water, dried over anhydrous sodium sulfate and the ether was evaporated. There was thus obtained 16a-trifiuoromethyl-A pregnene-3fi-ol-20-one.

A solution of 3.3 g. of the above compound in 250 ml. of acetic anhydride containing 1.3 g. of p-toluenesulfonic acid was subjected to a slow distillation over a period of 5 hours, the residue was poured into ice water and the product was extracted with ether. The extract was consecutively washed with 5% aqueous sodium carbonate solution and water, dried over anhydrous sodium sulfate and the ether was evaporated. There was thus obtained the diacetate of 16a-trifiuoromethyl-A pregnadiene-3fl,20diol, identical with the intermediate obtained in accordance with the method of Example 1.

EXAMPLE XIX The process described in the preceding example was applied to the acetate of 6-methyl-A -pregnadien-3B- ol-20-one and there was isolated as an intermediate 6- methyl 16cc trifluoromethyl A -pregnen-3B-ol-20-one, which was then converted into the diacetate of G-methyl- 16a-trifluoro-methyl-A -pregnadiene-3 5,20-di01, identical with the compound obtained in accordance with the method of Example XIV.

EXAMPLE XX To cc. of tetrahydrofuran containing approximately 3 g. of monofiuoromethylmagnesium iodide was added a solution of 5 g. of the acetate of A -pregnadien-3B- ol-ZO-one in 50 c. of tetrahydrofuran and 0.7 g. of cuprous chloride. The addition was effected under stirring over a period of 30 minutes, under an atmosphere of nitrogen and at a temperature between 20 and l0 C. The mixture was stirred for two more hours at 0 C.; it was cooled to -30 C. and 10 cc. of acetyl chloride were added. The temperature was allowed to reach 0 C. and the mixture was kept at this temperature for 20 minutes. There was then added 100 cc. of an aqueous saurated ammonium chloride solution followed by 30 cc. of aqueous concentrated sodium acetate solution. Extraction with methylene chloride followed by conventional purification 3.75 g. of 3,8,20-diacetoxy-16a-monofluoromethyl-A -pregnadiene.

For the next step there were combined several batches of the above compound.

A solution of 10 g. of 35,20-diacetoxy-16a-monofluoromethyl-A -pregnadien, in 100 cc. of ether, was treated with1300 cc. of a 1 N solution of monoperphthalic acid and the mixture was kept at room temperature for 3 days; at the end of this time it was consecutively washed with an aqueous solution of sodium chloride, sodium carbonate, sodium iodide and sodium thiosulfate and finally with sodium chloride; the ether solution was dried over anhydrous sodium sulfate and evaporated to dryness, thus yielding a mixture of 5a,6ot; 17,20-bis-oxido- 16a-monofiuoromethyl-3,ZO-diacetoxy-pregnane and of its 5,B,6 8isomer. This mixture was dissolved in 400 cc. of methanol, refluxed with 5.4 g. of potassium carbonate dissolved in 110 cc. of water, and refluxed for 1% hours; the mixture was neutralized with acetic acid, concentrated in vacuum to of its volume, poured int-o ice water and the precipitate formed was filtered and dried.

The above crude product was added to a mixture of 8.5 g. of sodium iodide, 2.8 g. of anhydrous sodium acetate, 8.5 g. of zinc dust, 33 cc. of acetic acid and 1.2 cc. of water; the mixture was stirred at room temperature for 3 hours, the zinc was removed by filtration and the solution was poured into ice water. The precipitate formed was collected, washed with water to neutrality, dried, dissolved in 200 cc. of hot dimethyl formamide, filtered through celite to remove traces of zinc and then hot water was added until crystallization; after cooling in ice and filtration, the precipitate was washed with methanol, and there was obtained 5 g. of 16OL-II1OI10flUOI'O- methyl-A -pregnen-3B,17u-dio1-20-one.

EXAMPLE XXI 5 g. of the above compound were dissolved in 50 cc. of acetone cooled to C., flushed with nitrogen and treated under stirring with 8 N chromic acid solution (as prepared in Example III) added in a thin stream, at 0 C., until the red color of chromium trioxide persisted in the mixture. After diluting the mixture with water theproduct was collected by filtration, Washed with water and dried under vacuum.

The crude product was dissolved in 200 cc. of methanol and treated at room temperature with a solution of 0.5 'g. of oxalic acid in cc. of water. The mixture was kept standing for 3 hours, then treated with water and the product was collected by filtration, washed with water to neutral and dried. There was thus obtained 16a-monoflnoromethyl-17a-hydroxy-A -pregnene-3,20-dione.

EXAMPLE XXII To a solution of 3.9 g. of 16a-monofloromethyl-17othydroxy-M-pregnene-3,20-dione in 30 cc. of tetrahydrofurane and 18 cc. of methanol was added under vigorous stirring 6 g. of calcium oxide and then 6 g. of metallic iodine; the stirring was continued at room temperature until the color of the solution became pale yellow, and then the mixture was poured into ice water containing cc. of acetic acid and 2.1 g. of sodium thiosulfate; the mixture was stirred for 15 minutes, most of the liquid was separated by decantation and the precipitate was collected, washed with water and dried under vacuum. There was thus obtained 16a-monofiuoromethyl-17a-hydroxy-2l-iodo-A -pregnene-3,20-dione.

The above substance was mixed with 25 cc. of anhydrous acetone and 4 g. of recently fused potassium acetate and refluxed for 8 hours, concentrated to a small volume under reduced pressure and diluted with waterjthe product was extracted with ether, washed with water, dried over anhydrous sodium sulfate and the ether was evaporated. Recrystallization of the residue from acetone-hexane yielded the 21-acetate of lzx-monofiuoromethyl-A pregnene-17u,21-diol-3,20-dione.

20 EXAMPLE XXIII A mixture of 1.16 g. of the above compound, cc. of t-butanol, 2 cc. of pyridine and 600 mg. of selenium dioxide was refluxed under an atmosphere of nitrogen for 72 hours; after cooling the mixture was diluted with ethyl acetate and filtered through celite; the filtrate was evaporated to dryness under reduced pressure, the residue was triturated with Water and the solid collected, washed with water and dried. Recrystallization from methylene chloride-hexane afforded 420 mg. of the 21-acetate of 16amonofluoromethyl A pregnadiene 17u,21 diol 3, 20-dione.

A solution of the above compound in 20 cc. of methanol was mixed with 4.6 cc. of a 1% solution of potassium hydroxide in water and stirred at 0 C. under an atmosphere of nitrogen for 1 hour; it was then neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected by filtration, washed with water, dried and recrystallized from ethyl acetate-methanol, thus giving approximately 375 mg. of l6a-monofiuoromethyl-A 17a,21-diol-3,20-dione.

EXAMPLE XXIV A solution of 4 g. of the acetate of 16a-monofiuoromethyl-A -pregnene-17a,21-diol-3,20-dione, obtained in accordance with the method of Example XXII, in cc. of methanol and 14 cc. of a 4% aqueous solution of potassium hydroxide was stirred for 1 hour under an atmosphere of nitrogen at 0 C.; the mixture was neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus producing 3.0 g. of l6ot-monofluoromethyl-M-pregnene-17a,21-diol- 3,20-dione.

EXAMPLE XXV To a polyethylene bottle containing 119 g. of anhydrous tetrahydrofuran was added 70 g. of anhydrous hydrogen fluoride. The mixture was cooled to 70 C. in a Dry Ice-acetone bath, and, under vigorous stirring there was added a mixture, previously cooled to 70 C., of 10 g. of l6ot-monofiuoromethyl-M-pregnene-3B,l7ot-diol-20-one (described in Example XX), and 5.0 g. of N-bromoacetamide in 350 ml. of anhydrous methylene chloride distilled over calcium chloride. The mixture was stirred at 70 C. for 5 hours, poured into aqueous saturated sodium carbonate solution and the precipitate was filtered. The organic layer was separated, the aqueous phase was extracted with several portions of methylene chloride and the extracts were combined, washed with water to neutrality, dried over anhydrous sodium sulfate, and evaporated to dryness under vacuum. The original precipitate and the residue of the evaporation were combined and crystallized from acetone, thus affording 9.3 g. of l6a-monofluoromethyl 5a bromo 65 fluoro pregnane 35,1704- diol-20-one.

EXAMPLE XXVI By applying the methods described in Examples IX through XI but substituting the 16bt-trifluoromethyl compound by the corresponding l6a-monofluoromethy1 compound described in the preceding example, there were obtained 21 EXAMPLE XXVII By substituting in the procedure described in Example XXII the 16a-monofl'uoromethyl-l7a-hydroxy-A -pregnene-3,20-dione by 6a-fluoro-16a-monofiuoromethyl-17ahydroxy-A -pregnene-3,ZO-dione, there was produced 6a-fluoro-16a-monofluoromethyl-17a-hydroxy-21-iodo- A -pregnene-3,20-dione and 6a-fluoro-16or-monofiuoromethyl-A pregnene-170,21-

diol-3 ,20-dione-2 l -acetate.

Upon treatment of the latter with methanolic potassium hydroxide as described in Example VI there was obtained 60: fluoro 16oz monofluoromethyl A pregnene 17a,- 21diol-3,20-dione.

EXAMPLE XXVIII By applying the method of dehydrogenation described in Example XXIII, 6a-fiuoro-l6a-monofluoromethyl-A pregnene-17a,21-diol-3,20-dione-21-acetate and the free alcohol thereof (described in the preceding example) were converted into the corresponding l-dehydro derivatives.

EXAMPLE XXIX The method of Examples XX through XXIII were repeated, starting from the acetate of the 6-methyl derivative of A -pregnadien-3B-ol-20-one. Thus there were obtained:

6-methyl-16a-monofiuoromethyl-35,20-diacetoxy- A -pregnadiene, the

3,20-diacetoxy-6-methyl-16a-monofluoromethyl-5,6;

17,20-bis-oxido-pregnane,

6-methyl-16or-monofluoromethyl-M-pregnane-3,6,17a-

diol-ZO-one,

6a-methyl-16a-monofluoromethyl-17a-hydroxy-A pregnene-3,20-dione, the

21-acetate of 6a-methyl-16a-monofluoromethyl-A -preg- 116116-17oc,21diOl-3,20-di0116, the

nadiene-17a,21-diol-3,20-dione and this last compound in form of the free alcohol.

EXAMPLE XXX A mixture of 10 g. of 16a-monofluoromethyl-A -pregnene'3fi,17adiol-20-one (cf. Example XX), 80 cc. of ethyleneglycol, 2 liters of dry benzene and 1.5 g. of monohydrated p-toluenesulfonic acid was refluxed for 18 hours, using a Dean-Stark water separator. The mixture was cooled, treated with a aqueous solution of sodium bicarbonate; the organic layer was separated, washed with water and dried over anhydrous sodium sulfate and the solvents were evaporated. Crystallization of the residue from acetone-hexane afforded la-monofluoromethyl-ZO- ethylenedioxy-A -pregnene-3 B, l7a-diol.

A solution of 8 g. of the above compound in 1600 cc. of methylene chloride was cooled to 0 C. and mixed with an ether solution of 4.0 g. of monoperphthalic acid. The mixture was kept at 0 C. for 16 hours, then diluted with water; the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutrality, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by crystallization from acetone-hexane. There was thus obtained 16a-monofluoromethyl-5 0:,6a-oxido-2Oethylenedioxy-pregnane-3 6,17a-di0l.

A mixture of 5 g. of the above compound and 5 molar equivalents of methylmagnesium bromide in 500 cc. of dry benzene was refluxed for 3 hours, then poured under vigorous stirring into a mixture of 1 liter of 20% aqueous ammonium chloride solution and 1 kg. of ice. The benzene layer was separated, the aqueous layer was extracted with benzene, both extracts were combined, washed with Water, dried over anhydrous sodium sulfate and the benzene was evaporated, finally under reduced pressure. The residue was treated with 100 mg. of p-toluenesulfonic acid monohydrate and 300 cc. of acetone and kept at room temperature for 16 hours, diluted with water and the solid collected, thus giving the crude 6,B-methyl16a-monofluoromethylpregnane-3B,5 11,1704 triol-2O one. The latter was oxidized with 8 N chromic acid, in accordance with the method described in Example III, to produce 6;?- methyl-16a-monofluoromethyI-pregnane-Sa,17ac-diol-3,20- dione, which, without further purification, was treated with 250 cc. of 1% methanolic potassium hydroxide under an atmosphere of nitrogen and at room temperature for 8 hours. After acidifying with acetic acid, the mixture was concentrated to a small volume under reduced pressure and the product was precipitated by the addition of water. The solid was collected, washed with water and crystallized from acetone-hexane. There was thus obtained 60:- methyl-'16a-monofiuoromethyl-A pregnen-17a-ol-3,20 -dione, identical with the intermediate of Example XXIX.

EXAMPLE XXXI 1 g. of 1a-monofiuoromethyl-17u-hydroxy-A pregnene-3,20-dione (Example XXI) was allowed to react overnight at room temperature with 5 cc. of acetic anhydride and 1 g. of p-toluenesulfonic acid in 50 cc. of acetic acid. The mixture was then poured into ice water and the solid formed was collected, washed with water, dried and treated with 50 cc. of 1% methanolic potassium hydroxide, under an atmosphere of nitrogen, at 5 C. for 4 hours. It was acidified with acetic acid, concentrated to a small volume and the precipitate was collected, washed with water, dried and crystallized from acetone-hexane. There was thus obtained 16tx-monofluoromethyl-17ot-acetoxy-A pregnene-3,2 0-dione.

By following the methods described abor e there was acetylated the 17a-hydroxyl group of the l6a-monofluoromeLhYI-6oc-flll0l'0 and 6a-1nethyl-16ot -monofluoromethyl derivatives of 17ot-hydroxy-A -pregnene-3,ZO-dione.

EXAMPLE XXXII A mixture of 1 g. of l5a-monofiuoromethyl-l7a-hydroxy-A -pregnene-3,20-dione, 3 g. of caproic anhydride, cc. of anhydrous benzene and 500 mg. of p-toluenesulfonic acid monohydrate was kept at room temperature for 48 hours, then abundantly washed with 5% aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the residue on neutral alumina followed by crystallization of the solid eluates from acetonehexane afforded the caproate of l6a-monofluoromethyl- 17a-hydroxy-A -pregnene-3 ,ZO-dione.

By the same method there were prepared the caproates of 16et-monofluoromethyl-6a-fluoro-17a-hydroxy-A -pregnene-3,20-dione and of 16a-monofluorornethyl-6u-methyl- 17ot-hydroxyA -pregnene-3,ZO-dione.

EXAMPLE XXXIII The reaction with monofiuoromethyl magnesium iodide described in Example XX was repeated, starting from 5 g. of the acetate of A -pregnadien-3B-ol-20-one, but without acetylating, the reaction mixture was poured into 1 l. of ice water containing 100 g. of ammonium chloride, the tetrahydrofuran was distilled and the aqueous residue extracted with several portions of ether. The extract was washed with water, dried over anhydrous sodium sulfate and the ether was evaporated. There was thus obtained 16a-monofluoromethyl-A -pregnen-3/3-ol-20-one. A solution of 3.3 g. of the above-mentioned compound in 250 ml of acetic anhydride containing 1.3 g. of p-toluene sulfonic acid was subjected to a slow distillation over a period of 5 hours, the residue was poured into ice water, and the product was extracted with ether. The extract was consecutively washed with 5% aqueous sodium carbonate solution and water, dried over anhydrous sodium sulfate and the ether was evaporated. Thus there was obtained the diacetate of 16a-mon0fluoromethyl-A pregnadien-3B,20-diol, identical with the intermediate obtained in accordance with the method of Example XX.

23 EXAMPLE XXXIV The process described in Example XXXIII was applied to the acetate of 6-methyl-A -pregnadien-3 8-ol-20-one and there was isolated as an intermediate 6-methyl-l6amonofluoromet hyl-A -pregnen-3,B-ol-20-one which was then converted into the diacetate of 6-methyl-16a-monofluoromethyl-A -pregnadien-3fl,20-diol, identical with the compound obtained in accordance with the method of Example XXIX.

EXAMPLE XXXV A solution of 5 g. of 16ot-trifluoromethyl-A -pregnene- 35,17-a-diol-20-one, obtained as described in Example II in 500 cc. of methylene chloride was cooled to C. and mixed with 1.5 molar equivalents of monoperphthalic acid in ether solution. The mixture was kept at 0 C. for 20 hours, diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 3.75 g. of the pure l6a-trifluoromethyl-a,6a-oxido-pregnan-3fl,17a-diol-20-one.

A solution of 3 g. of the above compound in 300 cc. of glacial acetic acid was treated with 6 cc. of concentrated hydrochloric acid and the mixture kept at room temperature for 6 hours. Aftre dilution with ice-salt water, and filtration of the formed precipitate there was obtained 16a-trifluoromethyl-6B-chloro-pregnane 3,851,170: triol- 20-one. Upon oxidation with 8 N chromic acid solution by following the method of Example III, there was obtained 16ct-trifluoromethyl-6B chloro-pregnane 5 a,17a diol-3,20-dione.

A slow stream of dry hydrogen chloride was introduced for 4 hours into a solution of '1 g. of the above compound in 100 cc. of glacial acetic acid, maintaining the temperature around 20 C.; the mixture was poured into ice water and the precipitate collected by filtration, washed with water, dried and recrystallized from acetone-ether thus yielding 6a-chloro-16u-trifluoromethyl-A -pregnen- 17oc-ol-3,20-dione. By following the procedure of Example XVI there was obtained t-he corresponding acetate.

EXAMPLE XXXVI A mixture of 1.5 g. of the above compound, 120 cc. of tertiary butanol, 2 cc. of pyridine and 600 mg. of selenium dioxide wasrefluxed under an atmosphere of nitrogen for 72 hours. After cooling, the mixture was diluted with ethyl acetate and filtered through celite; the filtrate was evaporated to dryness under reduced pressure, the residue was triturated with water and the solid collected, washed with water and dried. Recrystallization from methylene chloride-hexane afforded 6u-chloro-l6tx-trifluoromethyl- A -pregnadien-17u-ol 3,20 dione. Treatment of this compound with caproic anhydride in benzene solution and in the presence of p-toluene sulfonic acid gave the corresponding caproate.

EXAMPLE XXXVII To a solution of 1 g. of 6a-chloro-16a-trifluoromethyl- 17a-hydroxy-A -pregnene-3,20-dione in 7.5 cc. of tetrahydrofurane and 4.5 cc. of methanol was added under vigor- :ous stirring 1.6 g. of calcium oxide and then 1.6 g. of iodine; the stirring was continued at room temperature until the color of the solution became pale yellow and then the mixture was poured into ice water containing 4 cc. of acetic acid and 5 g. of sodium thiosulfate, stirred for minutes, most of the liquid was separated by decantation and the precipitate was collected, washed with water and dried under vacuum. There was thus obtained 6Ot-Ch' O1O-16Ottrifluoromethyl-17a-hydroxy-21-iodo-A pregnene 3,20- dione.

The above substancewas mixed with 50 cc. of anhydrous acetone and 4 g. of recently fused potassium acetate and refluxed for 8 hours, concentrated to a small volume under reduced pressure and diluted with water; the product separated by filtration and recrystallized from acetonehexane yielded the 2l-acetate of 6a-chloro-16a-trifluoromethyl-M-pregnene-l7a,2l-diol-3,20-dione.

EXAMPLE XXXVIII A mixture of 500 mg. of the above compound, 50 cc. of t-butanol, 0.75 cc. of pyridine and 200 mg. of selenium dioxide was refluxed under an atmosphere of nitrogen for 72 hours; after cooling the mixture was diluted with ethyl acetate and filtered through celite; the filtrate was evaporated to dryness under reduced pressure, the residue was triturated with water and the solid collected, washed with water and dried. Recrystallization from methylene chloride-hexane afforded 260 mg. of the 21-acetate of 6ot-chloro-l6a-trifluoromethyl-A pregnadiene 17oc,21- diol-3,20-dione.

EXAMPLE XXXIX A solution of the above compound in 10 cc. of methanol was mixed with 1.5 cc. of a 1% solution of potassium hydroxide in water and stirred at 0 C. under an atmosphere of nitrogen for 1 hour; it was then neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus giving 6ot-ChlOI'O-160t trifluoromethyl-A -pregnadiene 17a, 21-diol-3,20-dione.

EXAMPLE XL A mixture of 1 g. of l6a-trifiuoromethyl-l7uhydroxy A -pregnene-3,20-dione, 2 g. of chloranil and 50 cc. of terbutanol was refluxed for 8 hours. The mixture was cooled, the excess of chloranil filtered and washed with ethyl acetate and the organic extracts washed with a cold aqueous solution of 10% sodium hydroxide until the washings were colorless. It was then dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. Recrystallization from methylene chloride ether, after decloroization with 2 parts of alumina, gave 16OL-tl'lflll0l'0- methyl-A -pregnadien- 175-01-3 ,20-dione.

Treatment of the above componud with selenium dioxide in t-butanol solution and in the presence of pyridine in accordance with the method of Example V gave 16atrifluoromethyl-A -pregnat1'ien-17,8-01-3 ,20-dione.

EXAMPLE XLI The process described in the preceding example was applied to the acetate of 16tx-trifluoromethyl-M-pregnene- 17a,21-diol-3,20-dione, thus producing 16a-trifluoromethyl-A -pregnadien-lhfl1-diol-3,20-dione 2l-acetate and 16u-trifiuoro-methyl-A -pregnatrien 17a,21 diol-3.20- dione Zl-acetate. Upon treatment of the latter compound in methanol with potassium hydroxide, as described in Example VI, there was obtained 16a-trifluoromethyl-A -pregnatriene-17a,21-diol-3 ,20-dione.

EXAMPLE XLII By following the method of Example XL, 3 g. of 16a:- monofluoromethyl-l7a-hydroxy-A -pregnene 3,20 dione obtained in Example XXI was converted into 16a-monofluoromethyl-A -pregnadien-17a-ol-3,20-dione and 16amonofluoromethyl-A -pregnatrien-17a-ol-3 ,20-dione.

EXAMPLE XLIII A mixture of 1 g. of Got-fluoro-16a-trifluoromethyl-A pregne-17a-ol3,20-dione, 2 g. of chloranil, 15 cc. of ethyl acetate and 5 cc. of acetic acid was refluxed under an atmosphere of nitrogen for 96 hours. The mixture was cooled, washed with a cold aqueous solution of 10% sodium hydroxide until the washings were colorless, the organic solution was dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By chromatoggraphy of the residue on neutral alumina there was obtained the 6-fluoro-l6ot-trifluoromethyl A pregnadient-O1-3,20-dlOI1e.

By following the method of the preceding example 6a-iluoro-l6a-trifluoromethyl-A -pregnene 17a,21 diol- 3,20-dione 21-acetate obtained in Example XII and the corresponding A -dehydro derivative (of. Example XIII) were converted respectively into 6-fluoro-16a-trifiuoromethyI-A -pregnadiene-17a,21-diol-3,20-dione 21-acetate and 6-fiuoro-16a-trifluoromethyl A -pregnatriene-17a, 2l-diol-3,20-dione 21-acetate.

EXAMPLE XLV By following the method of Example XLIII, 6a-chloro- 16a-trifluoromethyl-A pregnene- 17a,2l-diol 3,20-dione 2l-monoacetate and 6ot-chloro-16atrifluoromethyl-A pregnadiene-17u,21-diol-3,20-dione were converted into 6-chloro-16tx-trifiuoromethyl-A -pregnadiene-17a,21-diol- 3,20-dione 2l-acetate and 6-chloro-16a-trifluoromethyl- A -pregnatrien-17 21-diol-3,20-dione.

EXAMPLE XLVI A solution of 5 g. of 16a-monofluoromethyl-17whydroxy-A -pregnene-3,20-dione obtained as described in Example XXII in 40 cc. of peroxide-free dioxane and 5 cc. of freshly distilled ethyl orthoformate was treated with 150 mg. of p-toluenesulfonic acid and the mixture stirred for 1 hour at room temperature. 0.8 cc. of pyridine was added and then poured into ice-salt water, the precipitate was collected and washed with water containing a few drops of pyridine, thus giving 16u-monofluoromethyl-3- ethoxy-A3,S-pregnadien-l7a-ol-20-one.

A mixture of the above enol ether, 2 g. of anhydrous sodium acetate, 100 cc. of acetone and 20 cc. of water was cooled to a temperature between and C.; there was then added 1.1 molar equivalents of N-chlorosuccinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C. for 30 minutes. It was then diluted with ice-salt water, kept standing overnight in the refrigerator and the precipitate formed was collected, washed with water, dried under vacuum and recrystallized from acetone. There was thus obtained a 6fl-chloro-16u-monofluoromethyl -A -pregnen-17a-ol-3 ,20- dione.

Into a solution of 1 g. of the above compound in 50 cc. of glacial acetic acid was passed a slow stream of dry hydrogen chloride for 4 hours, while maintaining the temperature around C.; the mixture was then poured into ice-water, the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane to give 6a-chloro-16a-monofluoromethyl -A -pregnen-l7a-ol- 3,20-dione.

EXAMPLE XLVII 1 g. of 6a-chloro-16a-monofiuoromethyl-A -pregnen- 17a-o1-3,20-dione was treated with acetic anhydride, in accordance with the method of Example XVI, thus giving 6a-chloro-16ot-monofluoroznethyl-A -pregnen l7oz-Ol- 3,20-dione acetate.

A mixture of 1 g. of the above compound, 2 g. of chloranil and 50 cc. of terbutanol was refluxed for 8 hours. The mixture was cooled, the excess of chloranil filtered and washed with ethyl acetate and the organic extracts washed with a cold aqueous solution of 10% sodium hydroxide until the washings were colorless. It was then dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. Recrystallization from methylene chloride ether, after decolorization with 2 parts of alumina, gave the acetate of 6-chloro-l6a-monofluoromethyl-A -pregnadienl t-Ol-3 ,20-dione.

EXAMPLE XLVIII By following the methods of Examples IV, V, and VI, 5 g. of 6a-chloro-l6a-monofluoromethyl-A -pregnen-17aol-3,20-dione were converted into 6ot-ChlOfO-l6ot-IHOI10- fluoromethyl-17whydroxy-21-iodo-A -pregnene 3,20-dione, 6a-chloro-16a-monofiuoromethyl-A -pregnene 17a, 21-diol-3,20-dione 2l-monoacetate, 60t-ChiOIO-16ll-Il'l0l'l0- fluoromethyl-A pregnadiene-17a,21-d-iol-3,20-dione 21- monoacetate and 60t-ChlOI'O-16OC monofluoromethyl-N pregnadiene-l7a,21-diol-3,20-dione.

EXAMPLE XLIX In accordance with the method described in our copending patent application Serial No. 63,266, filed on even date, now US. Patent No. 3,151,132, 5 g. of 16acyano A pregnen 3,8-01-20 one acetate described by J. Rome in Tetrahedron 3, 37 (1958) was reduced with sodium borohydride and the resulting ZO-hydroxy derivative was etherified by reaction with dihydropyran in benzene solution and in the presence of p-toluenesulfonic acid. The thus formed ZOB-tetrahydropyranyloxy-l6acyano-A -pregnen-3B-ol-acetate was hydrolized by refluxing with methanolic potassium hydroxide thus furnishing 2Ofl-tetrahydropyranyloxy-A -pregnen-3/3 ol-l6a-carboxylic acid. Upon treatment with benzoyl chloride in pyridine solution, there was obtained 3,8-benzoyloxy-20/3- tetrahydropyranyloxy-A -pregnene-16a carboxylic acid. Hydrolysis of the above compound with 2N hydrochloric acid, followed by treatment with acetic anhydride in pyridine gave 3fi-benzoyloxy-20fi acetoxy-A -pregnene 16ozcarboxylic acid.

A mixture of 1 g. of the abovementioned carboxylic acid and 5 cc. of oxalyl chloride was refluxed under anhydrous conditions during 2 hours. The solution was evaporated in vacuum, 2 portions of dry benzene were added and reevaporated to eliminate traces of oxalyl chloride. The above crude acid chloride was dissolved in 20 cc. of anhydrous tetrahydrofuran, cooled to C. in a Dry Ice-acetone bath and treated with a previously cooled solution of 600 mg. of lithium aluminum t-butoxide in 20 cc. of anhydrous tetrahydrofurane. The reaction mixture was kept at -75 C. for 1 hour and then at room temperature for 30 minutes, poured into ice water and extracted Several times with ethyl acetate, washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. After chromatography there was obtained the 3-benzoate 20- acetate of A -pregnene-3fi,20;3-diol-16a-carboxaldehyde.

EXAMPLE L A solution of 500 mg. of the above aldehyde in cc. of benzene was treated with 1 g. of sulfur tetrafiuoride and the mixture kept in a sealed steel tube for 48 hours at room temperature, it was then poured carefully into ice water. An excess of sodium bicarbonate was added and the product extracted with methylene chloride. The extract was washed with water to neutral, dried and evaporated to dryness. After chromatography and crystallization of the solid fractions from acet-onehexane there was obtained 16a-difluoromethyl A pregnene 35,205- diol-3-benzoate-20-acetate.

For the next step there were combined several batches of the above compound. A solution of 5 g. of the above compound in 200 cc. of methanol was treated with 2.5 g. of potassium carbonate dissolved in 20 cc. of water and the mixture was kept at room temperature for 12 hours. The reaction mixture was neutralized with acetic acid and concentrated under vacuum to one-third its volume,

2'7 poured into water, the formed precipitate filtered, washed with water to neutral and dried, thus giving 16x-difluoromethyl-A -pregnene-3 fl,20/3-diol-3-benzoate.

The above crude product was dissolved in 100 cc. of acetone, cooled to C. and treated dropwise under an atmosphere of nitrogen under stirring with an 8 N chromic acid solution (prepared as in Example VII) until the color of the reagent persisted in the mixture, stirred for 10 minutes further at room temperature, diluted with water and the precipitate collected, washed with water and dried under vacuum, thus afiording 16a-difluoromethyl-A -pregnen-3 {3-01-20-one benzoate.

The crude benzoate was dissolved in 75 cc. of methanol and refluxed for 3 hours with 2 g. of potassium hydroxide, it was then poured into ice water, the precipitate collected, washed with water to neutral, dried and recrystallized from ethyl acetate-ether, thus giving 3.5 g. of 160cdifluoromethyl-A -pregnen-3 ,8-ol-20-one.

EXAMPLE LI A sloution of 3 g. of l6ec-difluoromethyl-A -pregnen- 3,8-ol-20-one in 200 cc. of toluene and 50 cc. of cyclohexanone was dried by distilling off 30 cc. of the solvent, there was then added a solution of 3 g. of aluminum isopropoxide dissolved in 20 cc. of anhydrous toluene and the mixture was refluxed for 45 minutes, 10 cc. of acetic acid were added and the solvents removed by steam distillation. The product was extracted several times with ethyl acetate and the organic extracts washed with 5% hydrochloric acid solution, water, 10% sodium carbonate solution and water until neutral, dried over anhydrous sodium sulfate and evaporated until crystallization started. There was thus obtained 16a-difluoromethylprogesterone.

A solution of 3.3 g. of 16u-difluoromethyl-A -pregnen- 3/3-ol-20-one 3-benzoate in 250 ml. of acetic anhydride containing 1.3 g. of p-toluenesulfonic acid was subjected to slow distillation over a period of 8 hours, the residue was poured into ice water and the product was extracted with ether. The extract was consecutively washed with 5% aqueous sodium carbonate solution and water, dried over anhydrous sodium sulfate and the ether was evaporated. There was thus obtained 16u-difluoromethyl- A -pregnadiene-35,20-dio1-3-benzoate-20-acetate.

A solution of the above crude enol acetate in 30 cc. of ether was treated with 100 cc. of a 1 N solution of monoperphthal-ic acid and the mixture was kept at room temperature for 3 days; at the end of this time it was consecutively washed with dilute sodium chloride solution, sodium carbonate, sodium iodine, sodium thiosulfate and finally with sodium chloride solution; the ether solution was dried over anhydrous sodium sulfate and evaporated to dryness, thus yielding a mixture of 506,606-17,20-bl$ oxido-16a-difluoromethyl 3,8 benzoyloxy 20-ace-toxypregnane and of its 5 ,B,6fi-isomer. This mixture was dissolved in 150 cc. of methanol, treated with 1.5 g. of potassium hydroxide dissolved in cc. of water and refluxed for 3 hours; the mixture was neutralized with acetic acid, concentrated to one-third its volume, poured into ice water and the precipitate formed was collected and dried.

The above crude product was added to a mixture of 2.8 g. of sodium iodide, 0.95 g. of anhydrous sodium acetate, 2.8 g. of zinc dust, 11 cc. of acetic acid and 0.4 cc. of water; the mixture was stirred at room temperature for 3 hours, the zinc was removed by filtration and the solution was poured into ice water. The precipitate formed was collected, washed with water to neutrality, dried, dissolved in 70 cc. of hot dimethyl-formamide, filtered through celite to remove traces of zinc and then hot water was added to crystallize the product; after cooling in ice the precipitate was collected by filtration and washed with methanol, thus affording 1.6 g. of I60:- difluoromethyl-A -pregnene-3 5,17a-diol--0ne.

28 EXAMPLE LIII A solution of 1.5 g. of the above compound in 20 cc. of acetone was oxidized with an 8 N chromic acid solution in accordance with the method of Example III; the crude product was dissolved in 50 cc. of methanol and treated at room temperature with a solution of 150 mg. of oxalic acid in 1.5 cc. of water. The mixture was kept standing for 3 hours, then treated with water and the product was collected by filtration, washed with water to neutral and dried. There was thus obtained 16a-diflu'oromethyl-17ahydroxy-A -pregnene-3 ,20-dione.

Selenium dioxide oxidation of 500 mg. of the above compound, in accordance with the method of Example V, gave 16a-difluoromethyl-17u hydroxy-A -pregnadiene-3,20-dione.

EXAMPLE LIV A mixture of 500 mg. of 1606-dlfl1lOI'OIl'lCthYl-170t-hydroxy-progesterone, 10 cc. of dioxane and 350 mg. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refluxed for 18 hours. It was then cooled, the 2,3-dichloro-5,6- dicyano-1,4-benzohydroquinone formed during the reaction filtered off, and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 10 g. of alumina. Crystallization from acetone-hexane gave 16oc-difiuoromethyl 171x hydroxy-A -pregnadiene- 3,20-dione, identical with that obtained in the preceding example.

EXAMPLE LV By following the methods of Examples IV, V and VI, 1 g. of 16a-difluoromethy1-17a-hydroxy-M-pregnene-3,20- dione was converted into 16a-difluoromethyl-A -pregnene- 17,21 diol 3,20 dione 21-monoacetate, 16u-difluoromethyl-A -pregnadiene-17a,21-diol-3,2 0-dione 2l-monoacetate and l6u-difluoromethyl-A -pregnadiene-17a,21- diol-3,20-dione.

EXAMPLE LVI A mixture of 1 g. of 1Ga-difluoromethyl-17whydroxy- A -pregnene-3,2O-dione, 3 g. of cyclopentylpropionic anhydride, 100 cc. of anhydrous benzene and 500 mg. of p-toluenesulfonic acid monohydrate was kept at room temperature for 48 hours, then abundantly washed with 5% aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the residue on neutral alumina followed by crystallization of the solid eluates from acetonehexane afforded the cyclopentylpropionate of 16a-difluoromethyl- 17 whydroxy-A -pregnene-3,20-dione.

The above compound was treated with chloranil in t-butanol, in accordance with the method of Example XL thus giving the cyclopentylpropionate of 16oc-difill0f0- methyl-A -pregnadien-17u-ol-3,20-dione.

EMMPLE LVII By following the methods of Example VIII, IX and X, 1 g. of 16a-difluoromethyl-A -pregnene-35,17u-diol-20- one, obtained in Example LII, was converted into 604- fluoro-l 6a-difluoromethyl-M-pregnen-17oc-ol-3 ,20-dione.

500 mg. of the above compound were treated with 1.3 molar equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in accordance with the method of Example LIV, thus affording 6ot-fluoro-16a-difluoromethyl-N -pregnadien-17oc-ol-3,20-dione.

EXAMPLE LVIII By following the method of Example XXX, 3 g. of 16oc-difluoromethyl A pregnene-3f3,17u-diol-20-one obtained as described in Example LII, was converted in 6u-methyl-16a-difluoromethyl-M-pregnen 17m ol 3,201 dione.

A mixture of 1 g. of the above compound, 3 cc. of propionic anhydride, cc. of anhydrous benzene and 500 mg. of p-toluenesulfonic acid was kept at room temperature for 48 hours. After the usual work-up, including chromatography, there was obtained the propionate of 6a-methyl-l6a-trifluoromethyl-A pregnen-l7a-ol-3,20- dione. By following the method of Example XLVII the above compound was converted into 6-methyl-l6a-trifiuoromethyl-A -pregnadien 17ot-ol-3,20 dione propionate.

EXAMPLE LIX EXAMPLE LX To a solution of 1 g. of 6ot-methyl-l6rx-difiuoromethyl- 17ot-hydroxy-A -pregnene-3,ZO-dione in 75 cc. of tetrahydrofurane and 4.5 g. of methanol was added under vigorous stirring, 1.6 g. of calcium oxide and then 1.6 g. of iodine; the stirring was continued at room temperature until the color of the solution became pale yellow and then the mixture was poured into ice water containing 4 cc. of acetic acid and 500 mg. of sodium thiosulfate, stirred for 15 minutes, most of the liquid was separated by decantation and the precipitate was collected, washed with water and dried under vacuum. There was thus obtained 6OL-Il'16thy1 l6a-difiuoromethyl-l7a-hydroxy-2liodo-A -pregnene-3,20 dione.

The above substance was mixed with 50 cc. of anhydrous acetone and 3 g. of recently fused potassium acetate and refluxed for 8 hours, concentrated to a small volume under reduced pressure and diluted with water; the product was extracted with ether, washed with water, dried over anhydrous sodium sulfate and the ether was evaporated. Recrystallization of the residue from acetonehexane yielded the 21-acetate of 6vt-methyl-l6a-difluoromethyl-A -pregnene-l7a,21-diol-3,2O-dione.

By the same method, the 60t-fluOfO and 6u-chloro derivatives of 164x -difluoromethyl-l7a-hydroxy-A -pregnene-3,20-dione were converted respectively into 6a-fluoro- 16u-difiuoromethyl-M-pregnen-l7a,21-diol-3,20-dione 2lmonoacetate and 6a-chloro-16u-difluoromethyl-A -preg nen-l7a,2l-diol-3,20-dione 2l-monoacetate.

EXAMPLE LXI A solution of 500 mg. of the Zl-acetate of 6a-chlorol6a-difiuoromethyl-A -pregnene-l7a,21-diol-3,20-dione in 20 cc. of methanol was mixed with 5.0 cc. of a 1% solution of potassium hydroxide in water and stirred at C. under an atmosphere of nitrogen for 1 hour; it was then neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus giving approximately 430 mg. of 6ot-chloro-16a-difluoromethyl-A -pregnene-l7a,21-diol-3,20-dione. In the same manner, 6a-fluoro-l6a-difluoromethyl-A -pregnene-17a,2ldiol-3,20 -dione 2l-acetate and 6a-methyl-l6wdifluoromethyl-A -pregnene-l7a,21-diol-3,20-dione 21 monoacetate were converted into the corresponding free compounds.

EXAMPLE LXII In accordance with the method of Example V, 1 g. of the 21-acetate of 6 x-methyl-16ot-difluoromethyl-A pregnene-l7 x,21-diol-3,20-dione was treated with selenium dioxide to give the 21-acetate of 6OL-I1l6thYl-160t-dlflll0l0- methyl-a -pregnadiene-17,21 diol 3,20-dione. Upon treatment of the above compound with chloranil in mix- 30 ture with ethyl acetate and acetic acid in accordance with the method of Example XLIlI there was obtained 6- methyl 16a difiuoromethyl A pregnatriene-l7a,2ldiol-3,20-dione 2l-acetate.

EXAMPLE LXIII By following the esterification method of Example XVII, 1 g. of 6a-fluoro-l6a-difluoromethyl-A' -pregnenl7a-ol-3,20-dione obtained as described in Example LVII was converted into the corresponding caproate. Upon treatment with chloranil in terbutanol, in accordance with the method of Example XLVII, there was obtained the caproate of 6-fluoro-16ot-difluoromethyl-M -pregnadienl7a-ol-3,20-dione.

EXAMPLE LXIV By following the method of Example XXXV, 16amonofiuoromethyl A pregnene-3fi,l7adiol-20-one, obtained as described in Example XX, was converted into 6m chloro -16a-monofluoromethyl-A -pregen-17a-ol-3,20- dione. Chloranil dehydrogenation of the above compound, in accordance with the method of Example XLIII gave 6-chloro-16a-monofluoromethyl-A -pregnadien-17aol-3,20-dione.

The above compound was acetylated in accordance with the method of Example XVI, thus affording 6-chlorol6 monofluoromethyl-A -pregnadien-l7 ol 3,20-dione acetate.

EXAMPLE LXV wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between C-1 and C-2 and a saturated linkage between C-1 and C-2.

2. A compound of the folowing formula:

wherein R is selected from the group consisting of hydrogen' and a hydrogen carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between C-1 and C-2 and a saturated linkage between C-1 and C-2.

3. 6-methyl-16a-trifluoromethyl-M -pregnadien 17aol-3,20-dione propionate.

4. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between 0-1 and C-2 and a saturated linkage between 0-1 and C-2.

5. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between C-1 and C-2 and a saturated linkage between C-1 and C-2.

6. 6 chloro 16oc-difluoromethy A -pregnadien-17aol-3,20-dione-l7-acetate.

7. 6 fluoro-16u-difluoromethyl-A -pregnadien-17a-olcaproate.

8. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group con taining less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between C-1 and C-2 and a saturated linkage between C-1 and C2. Y

9. A compound of the following formula:

CHaOR" wherein R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between 0-1 and C2 and a saturated linkage between C-1 and C-2.

14. 60c methyl 16a-trifluoromethyl-A -pregnadiene- 17a,21-diol-3,20-dione.

15. 6a fluoro 16a-trifiuoromethyl-A -pregnadiene- 17u,21-diol-3,20-dione.

16. A compound of the following formula:

CHzOR wherein R and R" are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between 0-1 and C-2 and a saturated linkage between 0-1 and C-2.

/\I Z I wherein R and R" are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms, R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine and Z is selected from the group consisting of a double bond between 0-1 and C2 and a staurated linkage between 0-1 and C2.

18. 6a fluoro 16 a-difiuoromethyl-A -pregnadiene- 17a,21-diol-3,20-dione.

19. A compound of the following formula:

CH OR N I: T-CHFz 34 20. c fluoro-16a-difluoromethyl-M-pregnene-170;,21- diol-3,20-dione.

21. 6a chloro-16a-difluoromethyl-M-pregnene-l7a,2ldiol-3,20-dione.

22. A compound of the following formula:

CIJHZOR References Cited by the Examiner UNITED STATES PATENTS 2,902,483 9/1959 Agnello et al 260397.45 2,934,546 4/1960 Ringold et al. 260397.45 3,065,239 11/1962 Wendler et al. 260397.45 3,079,407 2/1963 Sarett et al. 260397.4

OTHER REFERENCES Fieser et al. Steroids (1959) Reinhold Publishing Corp. Pages 559-560 relied on.

Ringold et al. Journal Amer. Chem. Soc. (1959), pages 3485-6 relied on.

LEWIS GOTTS, Primary Examiner.

LESLIE H. GASTON, MORRIS LIEBMAN, Examiners. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 